STING调控血小板活化和脓毒症血栓形成的作用机制

Sepsis is a severe systemic inflammatory response syndrome caused by bacterial infection. Sepsis leads to coagulation dysfunction and facilitates the formation of disseminated intravascular thrombus, which is one of the main causes of multiple organ injury. As an effector cell of infection immunity, platelet plays an important role in septic thrombosis, but the mechanism of platelet in septic thrombosis still needs to be further studied. STING is an important pathogen-invading sensory protein in innate immune response. We found that STING specific agonists can significantly increase the activation of platelets, and STING deficiency inhibited platelet activation induced by agonists. STING deficiency in platelets markedly alleviated the formation of sepsis-induced multi-tissue intravascular thrombosis and mortality in mice. Therefore, we believe that platelet STING may be a key factor in the regulation of septic thrombosis. In this application, we will further elucidate the mechanism of STING pathway in platelet activation and septic thrombosis by using genetically modified animal models, as well as various biochemical and cellular biological techniques, and seek new approaches for the treatment of septic thrombosis.

脓毒症是细菌感染所致的严重全身炎症反应综合征。脓毒症可诱导凝血系统异常活化，促使弥散性血管内血栓的形成，这是造成多器官损伤的主要原因之一。血小板作为感染免疫的一种效应细胞，在脓毒症血栓形成中发挥重要作用，但对血小板在脓毒症血栓形成中作用机制仍需深入研究。STING是天然免疫反应中重要的病原体入侵的感应蛋白。我们研究发现STING特异性激动剂能够促进激动剂引发的血小板活化，并且STING缺失能够明显抑制激动剂诱导的血小板活化；STING缺失的血小板能够显著降低脓毒症诱发的小鼠多组织血管内血栓的形成以及小鼠死亡率。由此，我们认为血小板STING可能是调控脓毒症血栓形成的关键因素。在本申请中，我们将利用转基因动物和脓毒症模型，以及各种生化和细胞生物学技术，进一步阐明STING通路在血小板活化和脓毒症血栓形成中的作用机制，并针对该靶点寻找治疗脓毒症血栓的新手段。

血小板是感染免疫中的重要效应细胞，在感染性疾病、先天性免疫和炎症反应中发挥重要作用。脓毒症是一种严重的全身性炎症反应综合征，常导致弥散性血管内凝血（DIC）等凝血功能障碍，威胁生命健康。我们发现STING的特异性激动剂能显著增加血小板活化。同时，血小板中STING的缺乏明显降低脓毒症引起的多组织血管内血栓的形成，中性粒细胞胞外诱捕网（NETs）和小鼠死亡率。在机制上，我们发现STING可以特异性地与SNARE复合体的重要伴侣蛋白STXBP2结合，进而参与调控血小板颗粒释放的过程。据此，我们进一步研发了C-ST5多肽药，能显著抑制血小板活化和NETs生成，为临床治疗脓毒症血栓提供了全新的治疗手段。